WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke [see Contraindications (4)]. WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See Full Prescribing Information for complete boxed warning. Women over 35 years old who smoke should not use Lo Loestrin Fe (4) Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use (4)
1 INDICATIONS AND USAGE Lo Loestrin® Fe is indicated for use by women to prevent pregnancy [see Clinical Studies (14)]. The efficacy of Lo Loestrin Fe in women with a body mass index (BMI) of > 35 kg/m2 has not been evaluated. Lo Loestrin Fe is an estrogen/progestin COC indicated for use by women to prevent pregnancy (1) The efficacy of Lo Loestrin Fe in women with a body mass index of > 35 kg/m2 has not been evaluated (1, 8.8)
3 DOSAGE FORMS AND STRENGTHS Lo Loestrin Fe (norethindrone acetate and ethinyl estradiol tablets, ethinyl estradiol tablets and ferrous fumarate tablets) is available in blister packs. Each blister pack (28 tablets) contains in the following order: 24 blue, round (active) tablets imprinted with “WC” on one side and “421” on the other and each containing 1 mg norethindrone acetate and 10 mcg ethinyl estradiol. 2 white, hexagonal (active) tablets imprinted with “WC” on one side and “422” on the other and each containing 10 mcg ethinyl estradiol. 2 brown, round (non-hormonal placebo) tablets imprinted with “WC” on one side and “624” on the other and each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose. Lo Loestrin Fe consists of 28 tablets in the following order (3): 24 blue tablets (active), each containing 1 mg norethindrone acetate and 10 mcg ethinyl estradiol 2 white tablets (active), each containing 10 mcg ethinyl estradiol 2 brown tablets (non-hormonal placebo), each containing 75 mg ferrous fumarate. The ferrous fumarate tablets do not serve any therapeutic purpose
4 CONTRAINDICATIONS Do not prescribe Lo Loestrin Fe to women who are known to have the following conditions: A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)] Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions (5.1) ] Have cerebrovascular disease [see Warnings and Precautions (5.1)] Have coronary artery disease [see Warnings and Precautions (5.1)] Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions (5.1)] Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)] Have uncontrolled hypertension [see Warnings and Precautions (5.4)] Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.6)] Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings and Precautions (5.7)] Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.2)] Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.3)] Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.8)] Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)] A high risk of arterial or venous thrombotic diseases (4) Breast cancer or other estrogen- or progestin-sensitive cancer (4) Liver tumors or liver disease (4) Undiagnosed abnormal uterine bleeding (4) Pregnancy (4)
5 WARNINGS AND PRECAUTIONS Vascular risks: Stop Lo Loestrin Fe if a thrombotic event occurs. Stop Lo Loestrin Fe at least 4 weeks before through 2 weeks after major surgery. Start Lo Loestrin Fe no earlier than 4 weeks after delivery, in women who are not breastfeeding (5.1) Liver disease: Discontinue Lo Loestrin Fe if jaundice occurs (5.3) High blood pressure: Do not prescribe Lo Loestrin Fe for women with uncontrolled hypertension or hypertension with vascular disease (5.4) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Lo Loestrin Fe. Consider an alternative contraceptive method for women with uncontrolled dyslipidemia (5.6) Headache: Evaluate significant change in headaches and discontinue Lo Loestrin Fe if indicated (5.7) Uterine bleeding: Evaluate irregular bleeding or amenorrhea (5.8) 5.1 Thrombotic and Other Vascular Events Stop Lo Loestrin Fe if an arterial or deep venous thrombotic event occurs. Although use of COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of venous thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. The risk is highest during the first year of use of a COC. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued. If feasible, stop Lo Loestrin Fe at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start Lo Loestrin Fe no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest in older (> 35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with underlying risk factors. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors. Stop Lo Loestrin Fe if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. 5.2 Carcinoma of the Breast and Cervix Women who currently have or have had breast cancer should not use Lo Loestrin Fe because breast cancer is a hormonally-sensitive tumor. There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors. 5.3 Liver Disease Discontinue Lo Loestrin Fe if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases per 100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users. Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use. 5.4 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop Lo Loestrin Fe if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women with extended duration of use. The incidence of hypertension increases with increasing concentrations of progestin. 5.5 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. 5.6 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking Lo Loestrin Fe. COCs may decrease glucose tolerance in a dose-related fashion. Consider alternative contraception for women with uncontrolled dyslipidemias. A small proportion of women will have adverse lipid changes while on COCs. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. 5.7 Headache If a woman taking Lo Loestrin Fe develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Lo Loestrin Fe if indicated. An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC. 5.8 Bleeding Irregularities and Amenorrhea Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC. The clinical trial that evaluated the efficacy of Lo Loestrin Fe also assessed unscheduled bleeding and/or spotting. The participants in this 12-month clinical trial (N = 1,582 who had at least one post-treatment evaluation) completed over 15,000 cycles of exposure. A total of 1,257 women (85.9 percent) experienced unscheduled bleeding and/or spotting at some time during Cycles 2 to 13 of this study. The incidence of unscheduled bleeding and/or spotting was highest during Cycle 2 (53 percent) and lowest at Cycle 13 (36 percent). Among these women, the mean number of days of unscheduled bleeding and/or spotting during a 28-day cycle ranged from 1.8 to 3.2 days. Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over the one year study, with an average of less than 2 days per cycle. Women who are not pregnant and use Lo Loestrin Fe may experience amenorrhea (absence of scheduled and unscheduled bleeding/spotting). In the clinical trial with Lo Loestrin Fe, the incidence of amenorrhea increased from 32 percent in Cycle 1 to 49 percent by Cycle 13. If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Some women may experience amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was preexistent. 5.9 COC Use before or during Early Pregnancy Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral contraceptives are taken inadvertently during early pregnancy. Lo Loestrin Fe use should be discontinued if pregnancy is confirmed. Administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)]. 5.10 Depression Women with a history of depression should be carefully observed and Lo Loestrin Fe discontinued if depression recurs to a serious degree. 5.11 Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid binding globulin increase with use of COCs. 5.12 Monitoring A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare. 5.13 Other Conditions In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.
6 ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and smoking [see Boxed Warning and Warnings and Precautions (5.1)] Vascular events [see Warnings and Precautions (5.1)] Liver disease [see Warnings and Precautions (5.3)] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache The most common adverse reactions (≥ 2 percent) are nausea/vomiting (7 percent), headache (7 percent), bleeding irregularities (5 percent), dysmenorrhea (4 percent), weight change (4 percent), breast tenderness (4 percent), acne (3 percent), abdominal pain (3 percent), anxiety (2 percent) and depression (2 percent) (6) To report SUSPECTED ADVERSE REACTIONS, contact Warner Chilcott at 1-800-521-8813 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. A multicenter phase 3 clinical trial evaluated the safety and efficacy of Lo Loestrin Fe for pregnancy prevention. The study was a one year, open-label, single-arm, uncontrolled study. A total of 1,660 women aged 18 to 45 were enrolled and took at least one dose of Lo Loestrin Fe [see Clinical Studies (14)]. Common Adverse Reactions (≥ 2 percent of all Treated Subjects): The most common adverse reactions reported by at least 2 percent of the 1,660 women using Lo Loestrin Fe were the following in order of decreasing incidence: nausea/vomiting (7 percent), headache (7 percent), bleeding irregularities (including metrorrhagia, irregular menstruation, menorrhagia, vaginal hemorrhage and dysfunctional uterine bleeding) (5 percent), dysmenorrhea (4 percent), weight fluctuation (4 percent), breast tenderness (4 percent), acne (3 percent), abdominal pain (3 percent), anxiety (2 percent), and depression (2 percent). Adverse Reactions Leading to Study Discontinuation: 10.7 percent of the women discontinued from the clinical trial due to an adverse reaction. Adverse reactions occurring in ≥1 percent of subjects leading to discontinuation of treatment were in decreasing order: menstrual irregularities (including metrorrhagia, irregular menstruation, menorrhagia and vaginal hemorrhage) (4 percent), headache/migraine (1 percent), mood disorder (including mood swings, depression, anxiety) (1 percent), and weight fluctuation (1 percent). Serious Adverse Reactions: deep vein thrombosis, ovarian vein thrombosis, cholecystitis.
7 DRUG INTERACTIONS No drug-drug interaction studies were conducted with Lo Loestrin Fe. Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with COCs (7.1) 7.1 Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Products If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include: barbiturates bosentan carbamazepine felbamate griseofulvin oxcarbazepine phenytoin rifampin St. John’s wort topiramate HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma levels of the estrogen and progestin have been noted in some cases of co-administration of HIV protease inhibitors or of non-nucleoside reverse transcriptase inhibitors. Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. 7.2 Increase in Plasma Levels of Ethinyl Estradiol Associated with Co-Administered Drugs Co-administration of atorvastatin and certain COCs containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20 percent. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels. 7.3 Changes in Plasma Levels of Co-Administered Drugs COCs containing some synthetic estrogens (for example, ethinyl estradiol) may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.
8 USE IN SPECIFIC POPULATIONS Nursing mothers: Not recommended; can decrease milk production (8.3) 8.1 Pregnancy There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy. The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion. Women who do not breastfeed should not start COCs earlier than 4 weeks postpartum. 8.3 Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing OCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk. 8.4 Pediatric Use Safety and efficacy of Lo Loestrin Fe have been established in women of reproductive age. Safety and efficacy are expected to be the same in postpubertal adolescents under the age of 18 years as for users 18 years and older. Use of this product before menarche is not indicated. 8.5 Geriatric Use Lo Loestrin Fe has not been studied in postmenopausal women and is not indicated in this population. 8.6 Renal Impairment The pharmacokinetics of Lo Loestrin Fe has not been studied in subjects with renal impairment. 8.7 Hepatic Impairment No studies have been conducted to evaluate the effect of hepatic impairment on the disposition of Lo Loestrin Fe. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded [see Contraindications (4) and Warnings and Precautions (5.3)]. 8.8 Body Mass Index The safety and efficacy of Lo Loestrin Fe in women with a body mass index (BMI) > 35 kg/m2 has not been evaluated [see Clinical Studies (14)].